David Wotton

Education

  • BS, University of York, England
  • PhD, Imperial Cancer Research Fund, London

Primary Appointment

  • Associate Professor, Biochemistry and Molecular Genetics

Contact

Research Interest(s)

Regulation of Gene Expression, Development and Tumor Progression by TGF beta Signaling

Research Description

Analysis of the role of TGIFs during development.

TGIF proteins are transcriptional repressors, which regulate TGFβ signaling and have been suggested to repress retinoid regulated gene expression. Mutations in human TGIF are associated with holoprosencephaly (HPE), suggesting an important role in brain development and craniofacial morphogenesis. We have knocked out both Tgif1 and Tgif2 in mice and are analyzing defects in single and double mutant mice. We have shown that Tgif1;Tgif2 conditional double mutant mice develop HPE that is dependent on disruption of Sonic Hedgehog (Shh) signaling. We are currently analyzing the mechanisms by which loss of Tgifs and increased Nodal signaling affect the Shh pathway, cause HPE and regulate other early developmental proceses.

Molecular analysis of transcriptional repression by TGIFs.

We are analyzing the role that Tgifs play in regulating TGFβ activated gene expression and identifying target genes using transcriptome profiling by RNA-seq, from both embryos and cultured cells. In addition, we have begun to examine transcriptional repression by Tgifs via pathways other than TGFβ signaling. We have shown that Tgif1 represses gene expression via certain nuclear receptors, and have also identified a class of neural zinc finger transcription factors with which Tgif1 interacts. We are now actively trying to understand the importance of this interaction for neural development and differentiation. One interesting possibility that we are testing is that this link between Tgifs and neural zinc finger factors plays a role in the development of glioblastoma.

Analysis of the role of TGFβ signaling during prostate cancer progression.

Prostate cancer is the second leading cause of deaths due to cancer in North American men. We are testing how mutations in genes that are commonly found to be mutated in human prostate cancer cooperate to drive local prostate tumors to high grade invasive cancer. We have developed a novel prostate cancer mouse model, based on mutations in the Pten and Tgfbr2 tumor suppressor genes. We will determine how mutation of the Tgfbr2 gene allows primary tumors to become invasive and metastatic, and will use this model to test the efficacy of common therapeutic approaches to human prostate cancer. Additionally, we are exploring the pathways that are regulated by TGFβ in prostate that contribute to prostate cancer progression when the pathway is disrupted. Finally we are trying to generate better mouse models of prostate cancer that will better allow us to study metastasis.

Selected Publications

  • A CREB1-TGFβ2 Self-Sustaining Loop in Glioblastoma. Cancer discovery. 2014;4(10): 1123-5. PMID: 25274684
  • Bjerke G, Pietrzak K, Melhuish T, Frierson H, Paschal B, Wotton D. Prostate cancer induced by loss of Apc is restrained by TGFβ signaling. PloS one. 2014;9(3): e92800. PMID: 24651496 | PMCID: PMC3961420
  • Pramfalk C, Melhuish T, Wotton D, Jiang Z, Eriksson M, Parini P. TG-interacting factor 1 acts as a transcriptional repressor of sterol O-acyltransferase 2. Journal of lipid research. 2014;55(4): 709-17. PMID: 24478032 | PMCID: PMC3966704
  • Bjerke G, Yang C, Frierson H, Paschal B, Wotton D. Activation of Akt signaling in prostate induces a TGFβ-mediated restraint on cancer progression and metastasis. Oncogene. 2013. PMID: 23995785 | PMCID: PMC3939071
  • Yan L, Womack B, Wotton D, Guo Y, Shyr Y, Davé U, Li C, Hiebert S, Brandt S, Hamid R. Tgif1 regulates quiescence and self-renewal of hematopoietic stem cells. Molecular and cellular biology. 2013;33(24): 4824-33. PMID: 24100014 | PMCID: PMC3889555
  • TGF-β drives DNA demethylation. Molecular cell. 2012;46(5): 556-7. PMID: 22681884
  • Taniguchi K, Anderson A, Sutherland A, Wotton D. Loss of Tgif function causes holoprosencephaly by disrupting the SHH signaling pathway. PLoS genetics. 2012;8(2): e1002524. PMID: 22383895 | PMCID: PMC3285584
  • Zerlanko B, Bartholin L, Melhuish T, Wotton D. Premature senescence and increased TGFβ signaling in the absence of Tgif1. PloS one. 2012;7(4): e35460. PMID: 22514746 | PMCID: PMC3325954
  • Bjerke G, Hyman-Walsh C, Wotton D. Cooperative transcriptional activation by Klf4, Meis2, and Pbx1. Molecular and cellular biology. 2011;31(18): 3723-33. PMID: 21746878 | PMCID: PMC3165729
  • Hyman-Walsh C, Bjerke G, Wotton D. An autoinhibitory effect of the homothorax domain of Meis2. The FEBS journal. 2010;277(12): 2584-97. PMID: 20553494
  • Melhuish T, Chung D, Bjerke G, Wotton D. Tgif1 represses apolipoprotein gene expression in liver. Journal of cellular biochemistry. 2010;111(2): 380-90. PMID: 20506222 | PMCID: PMC2939915
  • Merrill J, Kagey M, Melhuish T, Powers S, Zerlanko B, Wotton D. Inhibition of CtBP1 activity by Akt-mediated phosphorylation. Journal of molecular biology. 2010;398(5): 657-71. PMID: 20361981 | PMCID: PMC2866129
  • Merrill J, Melhuish T, Kagey M, Yang S, Sharrocks A, Wotton D. A role for non-covalent SUMO interaction motifs in Pc2/CBX4 E3 activity. PloS one. 2010;5(1): e8794. PMID: 20098713 | PMCID: PMC2808386
  • Quijano J, Stinchfield M, Zerlanko B, Gibbens Y, Takaesu N, Hyman-Walsh C, Wotton D, Newfeld S. The Sno oncogene antagonizes Wingless signaling during wing development in Drosophila. PloS one. 2010;5(7): e11619. PMID: 20661280 | PMCID: PMC2905394
  • Vincent D, Kaniewski B, Powers S, Havenar-Daughton C, Marie J, Wotton D, Bartholin L. A rapid strategy to detect the recombined allele in LSL-TβRICA transgenic mice. Genesis (New York, N.Y. : 2000). 2010;48(9): 559-62. PMID: 20645310 | PMCID: PMC2944915
  • Powers S, Taniguchi K, Yen W, Melhuish T, Shen J, Walsh C, Sutherland A, Wotton D. Tgif1 and Tgif2 regulate Nodal signaling and are required for gastrulation. Development (Cambridge, England). 2009;137(2): 249-59. PMID: 20040491 | PMCID: PMC2799159
  • Bartholin L, Melhuish T, Powers S, Goddard-Léon S, Treilleux I, Sutherland A, Wotton D. Maternal Tgif is required for vascularization of the embryonic placenta. Developmental biology. 2008;319(2): 285-97. PMID: 18508043 | PMCID: PMC2517231
  • Chung D, Honda K, Cafuir L, McDuffie M, Wotton D. The Runx3 distal transcript encodes an additional transcriptional activation domain. The FEBS journal. 2007;274(13): 3429-39. PMID: 17555522
  • Wotton D, Merrill J. Pc2 and SUMOylation. Biochemical Society transactions. 2007;35 1401-4. PMID: 18031231
  • Bartholin L, Powers S, Melhuish T, Lasse S, Weinstein M, Wotton D. TGIF inhibits retinoid signaling. Molecular and cellular biology. 2006;26(3): 990-1001. PMID: 16428452 | PMCID: PMC1347013
  • El-Jaick K, Powers S, Bartholin L, Myers K, Hahn J, Orioli I, Ouspenskaia M, Lacbawan F, Roessler E, Wotton D, Muenke M. Functional analysis of mutations in TGIF associated with holoprosencephaly. Molecular genetics and metabolism. 2006;90(1): 97-111. PMID: 16962354 | PMCID: PMC1820763
  • Melhuish T, Wotton D. The Tgif2 gene contains a retained intron within the coding sequence. BMC molecular biology. 2006;7 2. PMID: 16436215 | PMCID: PMC1402312
  • Takaesu N, Hyman-Walsh C, Ye Y, Wisotzkey R, Stinchfield M, O'connor M, Wotton D, Newfeld S. dSno facilitates baboon signaling in the Drosophila brain by switching the affinity of Medea away from Mad and toward dSmad2. Genetics. 2006;174(3): 1299-313. PMID: 16951053 | PMCID: PMC1667060
  • Massagué J, Seoane J, Wotton D. Smad transcription factors. Genes & development. 2005;19(23): 2783-810. PMID: 16322555
  • Kagey M, Melhuish T, Powers S, Wotton D. Multiple activities contribute to Pc2 E3 function. The EMBO journal. 2004;24(1): 108-19. PMID: 15592428 | PMCID: PMC544918
  • Hyman C, Bartholin L, Newfeld S, Wotton D. Drosophila TGIF proteins are transcriptional activators. Molecular and cellular biology. 2003;23(24): 9262-74. PMID: 14645536 | PMCID: PMC309625
  • Kagey M, Melhuish T, Wotton D. The polycomb protein Pc2 is a SUMO E3. Cell. 2003;113(1): 127-37. PMID: 12679040
  • Lo R, Wotton D, Massagué J. Epidermal growth factor signaling via Ras controls the Smad transcriptional co-repressor TGIF. The EMBO journal. 2001;20(1): 128-36. PMID: 11226163 | PMCID: PMC140192
  • Melhuish T, Gallo C, Wotton D. TGIF2 interacts with histone deacetylase 1 and represses transcription. The Journal of biological chemistry. 2001;276(34): 32109-14. PMID: 11427533
  • Wotton D, Knoepfler P, Laherty C, Eisenman R, Massagué J. The Smad transcriptional corepressor TGIF recruits mSin3. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research. 2001;12(9): 457-63. PMID: 11571228
  • Wotton D, Massagué J. Smad transcriptional corepressors in TGF beta family signaling. Current topics in microbiology and immunology. 2001;254 145-64. PMID: 11190572
  • Gripp K, Wotton D, Edwards M, Roessler E, Ades L, Meinecke P, Richieri-Costa A, Zackai E, Massagué J, Muenke M, Elledge S. Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determination. Nature genetics. 2000;25(2): 205-8. PMID: 10835638
  • Massagué J, Wotton D. Transcriptional control by the TGF-beta/Smad signaling system. The EMBO journal. 2000;19(8): 1745-54. PMID: 10775259 | PMCID: PMC302010
  • Melhuish T, Wotton D. The interaction of the carboxyl terminus-binding protein with the Smad corepressor TGIF is disrupted by a holoprosencephaly mutation in TGIF. The Journal of biological chemistry. 2000;275(50): 39762-6. PMID: 10995736
  • Wotton D, Lo R, Lee S, Massagué J. A Smad transcriptional corepressor. Cell. 1999;97(1): 29-39. PMID: 10199400
  • Wotton D, Lo R, Swaby L, Massagué J. Multiple modes of repression by the Smad transcriptional corepressor TGIF. The Journal of biological chemistry. 1999;274(52): 37105-10. PMID: 10601270
  • Chen Y, Hata A, Lo R, Wotton D, Shi Y, Pavletich N, Massagué J. Determinants of specificity in TGF-beta signal transduction. Genes & development. 1998;12(14): 2144-52. PMID: 9679059 | PMCID: PMC317013
  • Hata A, Lo R, Wotton D, Lagna G, Massagué J. Mutations increasing autoinhibition inactivate tumour suppressors Smad2 and Smad4. Nature. 1997;388(6637): 82-7. PMID: 9214507
  • Marcand S, Wotton D, Gilson E, Shore D. Rap1p and telomere length regulation in yeast. Ciba Foundation symposium. 1997;211 76-93; discussion 93-103. PMID: 9524752
  • Wotton D, Shore D. A novel Rap1p-interacting factor, Rif2p, cooperates with Rif1p to regulate telomere length in Saccharomyces cerevisiae. Genes & development. 1997;11(6): 748-60. PMID: 9087429
  • Wotton D, Freeman K, Shore D. Multimerization of Hsp42p, a novel heat shock protein of Saccharomyces cerevisiae, is dependent on a conserved carboxyl-terminal sequence. The Journal of biological chemistry. 1996;271(5): 2717-23. PMID: 8576246
  • Kamoun M, Woods J, Sano N, Makni H, Smith R, de Lau W, van Oers A, Wotton D, Owen M, Hashimoto Y, Clevers H. Analysis of CD2 and TCR-beta gene expression in Jurkat cell mutants suggests a cis regulation of gene transcription. Journal of immunology (Baltimore, Md. : 1950). 1995;155(8): 3929-37. PMID: 7561100
  • Wotton D, Higgins J, O'Hehir R, Lamb J, Lake R. Differential induction of the NF-AT complex during restimulation and the induction of T-cell anergy. Human immunology. 1995;42(2): 95-102. PMID: 7744623
  • Wotton D, Lake R, Farr C, Owen M. The high mobility group transcription factor, SOX4, transactivates the human CD2 enhancer. The Journal of biological chemistry. 1995;270(13): 7515-22. PMID: 7706298
  • Wotton D, Ghysdael J, Wang S, Speck N, Owen M. Cooperative binding of Ets-1 and core binding factor to DNA. Molecular and cellular biology. 1994;14(1): 840-50. PMID: 8264651 | PMCID: PMC358432
  • Wotton D, Prosser H, Owen M. Regulation of human T cell receptor beta gene expression by Ets-1. Leukemia. 1993;7 S55-60. PMID: 8361234
  • Wotton D, Ways D, Parker P, Owen M. Activity of both Raf and Ras is necessary for activation of transcription of the human T cell receptor beta gene by protein kinase C, Ras plays multiple roles. The Journal of biological chemistry. 1993;268(24): 17975-82. PMID: 8349679
  • Prosser H, Wotton D, Gegonne A, Ghysdael J, Wang S, Speck N, Owen M. A phorbol ester response element within the human T-cell receptor beta-chain enhancer. Proceedings of the National Academy of Sciences of the United States of America. 1992;89(20): 9934-8. PMID: 1409722 | PMCID: PMC50248
  • Prosser H, Lake R, Wotton D, Owen M. Identification and functional analysis of the transcriptional enhancer of the human T cell receptor beta gene. European journal of immunology. 1991;21(1): 161-6. PMID: 1825057
  • Flanagan B, Wotton D, Tuck-Wah S, Owen M. DNase hypersensitivity and methylation of the human CD3G and D genes during T-cell development. Immunogenetics. 1990;31(1): 13-20. PMID: 2137107
  • Lake R, Wotton D, Owen M. A 3' transcriptional enhancer regulates tissue-specific expression of the human CD2 gene. The EMBO journal. 1990;9(10): 3129-36. PMID: 2209539 | PMCID: PMC552041
  • Wotton D, Flanagan B, Owen M. Chromatin configuration of the human CD2 gene locus during T-cell development. Proceedings of the National Academy of Sciences of the United States of America. 1989;86(11): 4195-9. PMID: 2567000 | PMCID: PMC287417
  • Lang G, Wotton D, Owen M, Sewell W, Brown M, Mason D, Crumpton M, Kioussis D. The structure of the human CD2 gene and its expression in transgenic mice. The EMBO journal. 1988;7(6): 1675-82. PMID: 2901953 | PMCID: PMC457152